Neurotransmitters

Question 1

Structure of neurones
What detects the input?
Where is info integrated?
Where is the AP generated?
How wide is synaptic cleft?
Features of axon terminal?
How long does synaptic transmission take?

Answer 1

Dendrites detect the input (covered in dendritic spines).
Information propagates down the dendrite and is integrated in the soma.
The AP is generated at the axon hillock.

The synaptic cleft is about 20-100nm wide.
There are lots of mitochondria in the axon terminal because energy is needed for NT release.
It takes ~2ms for the AP to get from one cell to the next.

Question 2

Mechanism of neurotransmission

Answer 2

1. AP propagates along membrane and the VGCCs activate.
2. Ca2+ enters the nerve terminal and exocytosis of NT is stimulated.
3. NT diffuses across the gap and interacts with the receptors.
4. The transmitter is then removed by the use of (for amino acid transmitters) by transporters.
   a. These take the amino-acid back into the terminal and
   other transporters take it back into the synaptic vesicles.
   b. Sodium-Potassium pumps then restore membrane
   potential.

Question 3

3 classes of neurotransmitter

Examples?

Answer 3

Amino Acids – e.g. Glutamate, GABA, glycine.
Amines – e.g. Noradrenaline, dopamine.
Neuropeptides – e.g. Opioid peptides.

Question 4

What is NT release dependent on?

Answer 4

▪ NT release requires an increase of intracellular Ca2+

Question 5

Vesicle release of neurotransmitter
Where are they before AP?
What allows them to stay there?
When AP arrives?

Answer 5

Vesicles are either:

i. Docked in the active zone at the site of synapse.
ii. Floating in the terminal region.

There is an interaction between the presynaptic membrane and the vesicle proteins, allowing the vesicle to be docked stably. There are alpha helical structures which interact together to form a super helix. This forms a stable complex of the vesicle at the synapse, full of NT. The vesicle then awaits the Ca2+ signal.

At these sites of docking, a large concentration of VGCCs exist and Ca2+ can enter which causes a calcium dependant change in a calcium sensor protein on the vesicle. The complex undergoes a conformational change and this drives the release of transmitter into the synaptic cleft

Question 6

Toxins that have an effect on synaptic vesicle proteins

Action?

Answer 6

▪ Tetanus – Spastic Paralysis – Zinc-dependant
endopeptidases that inhibit transmitter release.
▪ Botulinum – Flaccid Paralysis.
▪ Alpha Latrotoxin – Binds to protein at site of release and prevents the vesicle closing down and recycling, the NT is released to complete depletion.

Question 7

Transmitter release requires

Answer 7

Docking
Protein-complex formation
ATP and vesicle recycling

Question 8

Types of ion channel receptors
Properties
Examples?

Answer 8

1) Ion Channel Receptors – FAST (mediate ALL fast
excitatory and inhibitory transmission).
a. CNS: Glutamate, Gamma Amino Butyric Acid (GABA).
b. Neuromuscular Junction (NMJ): Acetylcholine (ACh) at nicotinic receptors.

2) G-protein Coupled Receptors – SLOW.
a. CNS and PNS: Acetylcholine at muscarinic receptors, Dopamine, Noradrenaline, 5-hydroxytryptamine, Neuropeptides (e.g. enkephalin).

Question 9

Glutamate
Features?
Formed from?
Mechanism?
Inactivation of glutamate once role= fulfilled?
If inactivation doesn't occur?
Types?

Answer 9

Excitatory – allows influx of Na+

Glutamate is formed from intermediary metabolism
(e.g. glycolysis and kreb’s cycle – formed from the
transamination of alpha-ketoglutarate).

It interacts with the receptor and causes entry of
sodium and calcium through the NMDA receptor.

Transporters on the pre-synaptic membrane and on
glial cells causes uptake of glutamate once it’s fulfilled
its role.
The main transporter is EAAT2 (Excitatory AminoAcid Transporter 2) which is found on glial cells
and on the pre-synaptic membrane.
Once in glial cells or in the neurones, glutamate is
then inactivated by glutamine synthetase to make
glutamine (addition of an amino-acid).

Abnormal cells firing leads to seizures associated with
excess glutamate in the synapse

1) AMPA Receptor:
a. Responsible for the majority of FAST excitatory
synapses.

2)NMDA Receptor:
a. SLOW component of the excitatory mechanism.
b. Needs TWO inputs for the receptor to become
activated:
• Membrane depolarised.
• Glutamate binding.
c. NMDA activation dependant on state of
depolarisation of the cell.
d. This also lets in calcium.

Question 10

GABA features
Synthesised by?
Mechanism?
Inactivation mechanism?

Answer 10

Inhibitory – allows influx of C

Glutamic Acid Decarboxylase (GAD) – Known as the Vitamin B6 enzyme.

GABA binds to the receptor and allows entry Cl- ions
which hyper-polarises the cell.

There are transporters on glial cells and on the presynaptic neurone which take up GABA (known as the
GABA transporters – GAT)
Once GABA has been taken up, it is inactivated by
GABA transaminase, giving Succinate semialdehyde
(which feeds into the TCA cycle).

Question 11

Epilepsy

Treating epilepsy? What can you produce? Binding site for?

Answer 11

Caused by abnormal release of glutamate leading to
hyper excitability of cells.

By exploiting the GABA receptor, you can produce antiepileptics, sedatives and muscle relaxants.
There is a binding site for:
o Benzodiazepines (e.g. diazepam).
o Barbiturates (e.g. for treatment of epilepsy – alters the
frequency of channel opening).